Each year approximately 200-300 million people experience a malarial illness in which over 1 million individuals die. In patients with severe and complicated disease, the mortality rate is between 20 and 50%. Plasmodium is the genus of protozoan parasites that is responsible for all cases of human malaria, and Plasmodium falciparum is the species of parasite that is responsible for the vast majority of fatal malaria infections. Malaria has traditionally been treated with quinolines such as chloroquine, quinine, mefloquine, and primaquine and with antifolates such as sulfadoxine-pyrimethamine. Unfortunately, most P. falciparum strains have now become resistant to chloroquine, and some strains, such as those found in Southeast Asia, have also developed resistance to mefloquine and halofantrine. Multidrug resistance to this species of parasites is also developing in Africa.
The endoperoxides are a promising class of antimalarial drugs that may meet the dual challenges posed by drug-resistant parasites and the rapid progression of malarial illness. The first generation endoperoxides include natural artemisinin and several synthetic derivatives. Artemisia annua L., also known as qinghao or sweet wormwood, is a pervasive weed that has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1972 Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This crystalline compound, called qinghaosu, also referred to as QHS or artemisinin, is a sesquiterpene lactone with an internal peroxide linkage as shown below:

Artemisinin is a member of the amorphane subgroup of cadinenes. This compound was the subject of a 1979 study conducted by the Qinghaosu Antimalarial Coordinating Research Group involving the treatment of 2099 cases of malaria (P. vivax and P. falciparum in a ratio of about 3:1) with different dosage forms, leading to the clinical cure of all patients (Qinghaosu Antimalarial Coordinating Research Group, Chin. Med. J., 92:811 (1979)). Since that time artemisinin has been used successfully in many thousand malaria patients throughout the world including those infected with both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. Assay of artemisinin against P. falciparum in vitro revealed that its potency is comparable to that of chloroquine in two Hanian strains (Z. Ye, et al., J. Trad. Chin. Med., 3:95 (1983)) and of mefloquine in the Camp (chloroquine-susceptible) and Smith (chloroquine-resistant) strains (D. L. Klayman, et al., J. Nat. Prod., 47:715 (1984)).
Although artemisinin is effective at suppressing the parasitemias of P. vivax and P. falciparum, the problems encountered with recrudescence, and the compound's insolubility in water, led scientists to modify artemisinin chemically, a difficult task because of the chemical reactivity of the peroxide linkage which is believed to be an essential moiety for antimalarial activity. These modifications include the reduction of artemisinin to dihydroartemisinin or DHQHS, in which the lactone group is converted to a lactol (hemiacetal) function, and which has similar properties to artemisinin. Dihydroartemisinin may also be converted to a large number of other derivatives, such as artemether, arteether, sodium artesunate, artelinic acid, sodium artelinate, and dihydroartemisinin (R. Haynes, Transactions of the Royal Society of Tropical Medicine and Hygiene, 88(1): S1/23-S1/26 (1994); Brossi, et al., 1988; M. Cao, et al., Chem. Abstr., 100:34720k (1984)).
Other rational design of structurally simpler analogs of artemisinin has led to the synthesis of various trioxanes, some of which possess excellent antimalarial activity. For example, Posner, G. H., et al., reported the chemistry and biology of a series of new structurally simple, easily prepared, racemic 1,2,4-trioxanes as disclosed in U.S. Pat. No. 5,225,437; U.S. patent application Ser. No. 10/529,513; and in Posner, G. H., et al., J. Med. Chem., 35:2459-2467 (1992), the disclosure of each of which are hereby incorporated herein by reference in their entirety for all purposes. Jung, M., et al., has also reported on the antitumor activity of dimeric deoxyartemisinin derivatives with alkylamide and sulfur linkers of various lengths and flexibility (Journal of Medicinal Chemistry, 2003, Vol. 46, No. 6, 987-994). The complete chemical synthesis of artemisinin and a variety of other derivatives is reviewed by Sharma, R. P., et al., Heterocycles, 32(8):1593-1638 (1991), and is also incorporated herein by reference. Unfortunately, most C-10 acetal derivatives are often unstable in water, i.e. they are easily hydrolyzed. Therefore making hydrolytically stable C-10 non-acetal carba-derivatives has become a high priority.
Since the isolation of artemisinin, there has been a concerted effort by investigators to study other therapeutic applications of artemisinin and its derivatives. The National Institutes of Health reported that artemisinin is inactive against P388 leukemia (NCI Report on NSC 369397, tested on 25 Oct. 1983). Later anticancer studies that have been conducted on cell line panels consisting of 60 lines organized into nine, disease-related subpanels including leukemia, non-small-cell lung cancer, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers, further confirm that artemisinin displays modest anticancer activity.
While artemisinin and its related derivatives demonstrate zero to slight antiproliferative and antitumor activity, it has been discovered that a class of artemisinin dimer compounds exhibits antiproliferative and antitumor activities that are, in vitro, equivalent to or greater than known antiproliferative and antitumor agents (U.S. Pat. No. 5,677,468 also incorporated herein by reference in its entirety for all purposes). Unfortunately, while the in vitro results of these artemisinin compounds are encouraging, these compounds do not appear to have as significant antitumor activity on the treatment of tumor cells in mice.
There is still a need, therefore, to develop stable artemisinin derivatives and structural analogs thereof having antimalarial, anticancer, antiproliferative, and antitumor activities that are equivalent to or greater than those of known antimalarial, anticancer, antiproliferative and antitumor agents, respectively.